Pulsed field ablation (PFA) has demonstrated favorable safety and efficacy in atrial fibrillation ablation, particularly for pulmonary vein isolation (PVI). However, the optimal PFA-based ablation strategy for non-paroxysmal atrial fibrillation remains uncertain. In addition to anatomical lesion sets such as PVI and posterior wall isolation (PWI), Electrogram Mapping of Key Substrates may allow identification of residual arrhythmogenic areas that contribute to the maintenance of atrial fibrillation. In the investigators' previously completed single-center cohort study, adjunctive ablation targeting key substrates identified by electrogram mapping on top of PVI+PWI was feasible and associated with improved rhythm outcomes.

This prospective multicenter randomized controlled study is designed to compare PFA-based PVI+PWI alone versus PVI+PWI plus adjunctive ablation guided by Electrogram Mapping of Key Substrates in patients with non-paroxysmal atrial fibrillation, in order to evaluate the efficacy and safety of this strategy in a broader and more rigorous clinical setting.

Pulsed field ablation (PFA) has emerged as a promising energy source for atrial fibrillation ablation because of its myocardial selectivity and favorable safety profile. Previous studies have demonstrated high procedural success and encouraging clinical outcomes for PFA-based pulmonary vein isolation (PVI), particularly in patients with paroxysmal atrial fibrillation. However, in patients with non-paroxysmal atrial fibrillation, the underlying arrhythmogenic substrate is often more complex and extends beyond the pulmonary veins, and the optimal lesion set for PFA-based ablation in this population remains to be established.

Posterior wall isolation (PWI) is commonly added to PVI in an effort to improve substrate modification in non-paroxysmal atrial fibrillation. Nevertheless, recurrence after PVI+PWI remains common, suggesting that additional mechanisms outside conventional anatomical targets may play an important role in arrhythmia maintenance. Electrogram Mapping of Key Substrates provides a strategy to identify localized abnormal electrophysiological regions that may represent critical drivers or perpetuators of atrial fibrillation and may therefore serve as adjunctive ablation targets beyond standard anatomical lesion sets.

In the investigators' previous studies of catheter ablation for persistent atrial fibrillation, substrate modification guided by electrogram characteristics showed promising efficacy. More specifically, in the investigators' completed single-center cohort study of PFA for non-paroxysmal atrial fibrillation, adjunctive ablation based on Electrogram Mapping of Key Substrates in addition to PVI+PWI was shown to be feasible and was associated with favorable rhythm control outcomes. These findings support the hypothesis that a strategy incorporating electrogram-defined key substrate identification may provide incremental benefit over PVI+PWI alone.

However, whether adjunctive ablation guided by Electrogram Mapping of Key Substrates improves clinical outcomes in a reproducible manner has not yet been validated in a prospective multicenter randomized controlled trial. Given the potential influence of operator experience and center-level variability on substrate-based ablation, a multicenter randomized design is necessary to provide more robust evidence regarding the efficacy, safety, and generalizability of this strategy.

Therefore, the present study is designed as a prospective multicenter randomized controlled trial to compare two PFA-based ablation strategies in patients with non-paroxysmal atrial fibrillation:

1. PVI+PWI alone; and
2. PVI+PWI plus adjunctive ablation guided by Electrogram Mapping of Key Substrates.

The primary objective of this study is to determine whether the addition of ablation targeting key substrates identified by electrogram mapping improves rhythm outcomes compared with PVI+PWI alone. The study will also assess procedural characteristics and safety outcomes to further define the role of Electrogram Mapping of Key Substrates in optimizing PFA-based ablation strategies for non-paroxysmal atrial fibrillation.

Inclusion Criteria:

• 1. Patients with documented drug-resistant symptomatic persistent AF meeting all three of the following criteria:a. Patient is refractory or intolerant to at least one Class I/III antiarrhythmic agentb. ECG-documented episode of persistent AF lasting longer than 7 days c. Holter within 90 days of the Enrollment Date demonstrating 24 hours of continuous AF2. Patients who are ≥ 18 years and <80 years 3. Patient participation requirements:a. Is willing and capable of providing Informed Consent to undergo study proceduresb. Is willing to participate in all examinations and follow-up visits and tests associated with this clinical study.

Exclusion Criteria:

• 1. AF that is:a. Paroxysmal (longest AF episode < 7days)b. Secondary to electrolyte imbalance, thyroid disease, alcohol abuse or other reversible / non-cardiac causes2. Left atrial anteroposterior diameter ≥ 60 mm as documented by transthoracic echocardiography (TTE) or computed tomography (CT)3. Any of the following cardiac conditions:a. Clinically significant arrhythmias other than AF, AFL or ATb. NYHA Class IV CHFc. Atrial or ventricular septal defect closured. Atrial myxomae. History of congenital heart disease with any residual anatomic or conduction abnormality4. Any of the following within 3 months of enrollment:a. Myocardial infarctionb. Unstable anginac. Percutaneous coronary interventiond. Heart surgery (e.g. coronary artery bypass grafting, ventriculotomy, atriotomy)e. Heart failure hospitalizationf. Stroke or TIAg. Clinically significant bleedingh. Pericarditis or pericardial effusioni. Left atrial thrombus 5. History of blood clotting or bleeding abnormalities.6. Contraindication to, or unwillingness to use, systemic anticoagulation 7. Sensitivity to contrast media not controlled by premedication8. Women of childbearing potential who are pregnant, lactating or not using birth control9. Medical conditions that would prevent participation in the study, interfere with assessment or therapy, significantly raise the risk of study participation, or confound data or its interpretation, including but not limited toa. Body mass index (BMI) > 40 transplantb. Severe lung disease, pulmonary hypertension, or any lung disease involving abnormal blood gases or significant dyspneac. Renal insufficiency with an estimated creatinine clearance < 30 mL/min/1.73 m2, or any history of renal dialysis or renal transplant d. Active malignancy or history of treated cancer within 24 months of enrollmente. Clinically significant gastrointestinal problems involving the esophagus, stomach and/or untreated acid refluxf. Clinically significant infectiong. Predicted life expectancy less than one year10. Current or anticipated enrollment in any other clinical study

The individual participant data (IPD) from this study will not be shared publicly due to concerns regarding patient confidentiality and the sensitive nature of medical data. Given the potential risks of identifying participants from detailed clinical information, the data will remain confidential and will not be made available for public sharing. Additionally, the study involves proprietary methodologies and ongoing analyses that are part of the intellectual property of the institution. As such, sharing the IPD at this stage could compromise the integrity of the study's findings and its future applications.